DESCRIPTION: (Applicant's Abstract) The management of pain and inflammation are too often unpredictable, with many patients reporting little-to-no relief with most available drugs. Therefore, research into novel drug mechanisms may offer potentially new clinically useful therapeutic agents. We propose to evaluate the hypothesis that cannabinoids, known to have central antinociceptive actions, also act in the periphery to modulate the activity of terminals of certain nociceptors. Such peripheral actions of cannabinoids would be physiologically and clinically significant, since inhibition of nociceptive primary afferent neurons could alter both peripheral secretion of neuropeptides (reducing neurogenic inflammation), and, possibly, membrane depolarization (inhibiting hyperalgesia). Specifically, we will test the hypothesis that cannabinoids modulate the development of neurogenic inflammation by inhibiting activation of peripheral terminals of capsaicin-sensitive primary afferent fibers, as measured by peripheral release of the pro-inflammatory neuropeptide calcitonin gene-related peptide (CGRP). Our research strategy takes advantage of a uniquely innervated tissue: dental pulp. Application of any physiologic stimulus to human dental pulp, including thermal, osmotic, chemical or mechanical, produces only a pain sensation. Thus, virtually all sensory neurons which innervate pulp appear to be nociceptors. Accordingly, application of drugs to pulpal sensory neurons targets a population of sensory neurons consisting predominantly of nociceptors. Our specific aims will: 1. Characterize the pharmacological effects of cannabinoids to modulate the development of neurogenic inflammation, as measured by inhibition of iCGRP secretion from superfused dental pulp. 2. Evaluate the molecular basis for cannabinoids to directly modulate iCGRP release via interaction with receptors expressed on peptidergic trigeminal sensory neurons. 3. Determine whether cannabinoid inhibition of iCGRP release is mediated by a direct mechanism (i.e., activation of sensory neuronal cannabinoid receptors), by an indirect mechanism (i.e., activation of receptors expressed on autonomic fibers or non-neuronal cells in pulp), or by a combination of the two. Since dental pulp is innervated primarily by nociceptors and is frequently involved with inflammation and healing, this tissue is a relevant biomedical model system. Moreover, the use of specific pharmacological, immunological and molecular probes for cannabinoids should contribute to an understanding on a biochemical level for the effects of cannabinoids on sensory neurons and open new avenues of research on the peripheral actions of these compounds. This knowledge base may provide a rationale for developing peripherally-selective cannabinoid analgesics with minimal CNS-mediated side-effect liability.